Cancer affects the lives of millions of people on a global basis. Treatments such as chemotherapy produce beneficial results in some malignancies, however, some cancers, including lung, pancreatic, prostate, and colon cancers, demonstrate poor response to such treatments. Further, even cancers initially responsive to chemotherapy can return after remission, with widespread metastatic spread leading to death of the patient. In addition, chemotherapy agents, e.g., antineoplastic agents, have significant toxicities, and are associated with side effects including, e.g., bone marrow suppression, renal dysfunction, stomatitis, enteritis, and hair loss. Therefore, there is a need for effective and safe therapies for treatment of cancer, prevention of metastasis, etc.
Connective Tissue Growth Factor (CTGF) is a growth factor with demonstrated effects in various physiological and pathological contexts, including mitogenic and chemotactic processes, and the production of extracellular matrix components. CTGF has been implicated in a number of disorders and conditions, including, but not limited to, disorders involving angiogenesis, fibrosis, and other conditions with proliferative aspects. CTGF has been previously identified as a critical factor associated with tumor formation and growth, and is overexpressed in a variety of tumor types. (See, e.g., International Publication No, WO 96/38172; Wenger et al. (1999) Oncogene 18:1073-1080; Xie et al. (2001) Cancer Res 61:8917-8923; Igarashi et al. (1998) J Cutan Pathol 25:143-148; Kasaragod et al. (2001) Ped Dev Pathol 4:37-45; Shalcunaga et al. (2000) Cancer 89:1466-1473; Vorwerk et al. (2000) Br J Cancer 83:756-760; Pan et al. (2002) Neurol Res 24(7):677-683.) CTGF is also known to have pro-angiogenic activity in vivo, an important process associated with tumor survival. (See, e.g., Brig (2002) Angiogenesis 5:153-165; Shimo et al, (1999) J Biochem 126:137-145; Babic et al. (1999) Mol Cell Biol 19:2958-2966; Ivkovic et al. (2003) Development 130:2779-2791; and Shinto et al. (2001) Oncology 61:315-322.)
However, correlation between CTGF expression and prognosis in cancer patients has suggested a context specific role for the protein. For example, CTGF expression was associated with longer patient survival in squamous cell carcinomas, but decreased survival in esophageal adenocarcinomas. (Koliopanos et al. (2002) World J Surg 26:420-427.) Similarly, CTGF has been implicated in increased apoptosis of, e.g., breast cancer cells, and increased survival of, e.g., rhabdomyosarcoma cells. (See, e.g., Hishikawa et al. (1999) J Biol Chem 274:37461-37466; Croci et at (2004) Cancer Res 64:1730-1736.) Therefore, there is a need for improved understanding of cancer-associated CTGF-related effects, and for methodologies appropriately targeting CTGF within the context of the disease.
In summary, there is a need in the art for effective treatments for cancer, and, specifically, there is a need for methods of selective treatment that effectively targets CTGF-related or -induced aspects of cancer. The present invention meets these needs by providing methods for reducing tumor survival, expansion, and metastasis, and, in particular, by providing methods for reducing pancreatic tumor survival, expansion, and metastasis. The invention also provides agents for use in the methods, particularly reagents that reduce the level or activity of CTGF, and methods for identifying such agents.